Abnormal accumulation of amyloid β protein (Aβ) in brain is implicated in the molecular pathogenesis of Alzheimer's disease (AD). Therefore, decreasing Aβ is expected to serve as a treatment of Alzheimer's disease based on the pathological condition.
Aβ is produced in neuron cells by a two-step proteolytic processing of the amyloid-β precursor protein (APP). The initial cleavage at the extracellular juxtamembrane site is mediated by the β-secretase, and yields the secretory N-terminal ectodomain (sAPPβ) and the membrane-spanning C-terminal fragment (APP-CTFβ or APP-C99). Then, the intramembranous aspartyl protease γ-secretase (a macromolecular complex comprised of four core components: presenilin, nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2)) further proteolyzes APP-C99 to Aβ and the APP intracellular domain (AICD) (see FIG. 4). For APP-C99 proteolysis, a pathway that does not involve Aβ generation is also known.
In the development of the therapeutic strategy for Alzheimer's disease, γ-secretase activity inhibitors have been mainly used as a method for reducing Aβ generation from APP. Although many inhibitors have been developed, the clinical trials revealed that administration of γ-secretase inhibitors caused side effects such as worsening of dementia or increase in frequency of occurrence of skin cancer, presumably due to intracellular accumulation of APP-C99 and failure of cleavage of Notch protein that serves as a substrate as with APP.
Patent Document 1 discloses a biomarker for Alzheimer's disease. More specifically, Patent Document 1 is an invention that relates to a method for qualifying a state of Alzheimer's disease in a test subject; the method comprising (a) a step of measuring at least one biomarker in a biological material obtained from the test subject, wherein the at least one biomarker is selected from saposin D(I), saposin D(II), saposin D(III) and FAM3C(I); and a step (b) of relating the measurement result with a state of Alzheimer's disease.
However, Patent Document 1 merely discloses using the four kinds of protein as biomarkers for Alzheimer's disease, and nowhere discloses other uses thereof.